PROJECT SUMMARY Advancing medications development is a critical objective in reducing health and societal burdens associated with alcohol use disorder (AUD. Recently, priority has been placed on human laboratory paradigms as an efficient and cost-effective method for screening new candidate therapies. In addition to the efficiency of this approach, an advantage of human laboratory screening trials is the ability to examine medication effects on alcohol-related behaviors analogous to those studied in animal studies (e.g., operant responding, self- administration), maximizing correspondence between human and animal studies. Animal studies have implicated histamine H3 receptors in alcohol intake, motivation, and reinstatement. For example, alcohol consumption was reduced in mice lacking the H3 receptor, and H3 antagonists decreased alcohol intake and effort to obtain alcohol in an animal model of alcohol dependence. Recently, novel H3 antagonists have been developed, representing potential therapies for the indication of alcohol use disorder. The purpose of the present proposal is to conduct an initial trial of a new H3 antagonist medications in humans with AUD. Specifically, this project proposes a randomized medication screening trial with human laboratory components. Non-treatment-seeking participants with AUD will participate in medication and placebo treatment phases in a randomized, counter-balanced fashion, with laboratory sessions occurring at the conclusion of each phase. To maximize experimental control, the laboratory component of this study will utilize intravenous (IV) alcohol administration paradigms. Additionally, to maximize comparability with animal models, laboratory paradigms will be analogous to those used in animal studies of H3 antagonists. This project will allow for the first human medication screening trial of H3 antagonist treatments in participants with AUD. Our long-term goal is to facilitate the translation of basic science discoveries in clinical validation studies by establishing an efficient process for conducting human screening studies of candidate therapies for AUD.